CA2093507A1 - Process for preparing 7-substituted-amino-3-hydroxy-3-cephem-4-protected carboxy-sulfoxide esters - Google Patents

Abstract

X-8728(EPO) Abstract A process for the conversion of a 4-chlorosulfonyl azetidinone (a) to a 3-hydroxy-3-cephem-sulfoxide ester (d) by subjecting an intermediate comprising a tin containing Lewis acid-type Fiedel-Crafts catalyst and 3-exomethylene cepham to ozonolysis.

Description

~ $~ P~
x-8728 -1-HY~ROXY-3-CEPHEM-4-PROTECTED CARBOXY -SULFOXIDE ESTERS

Back~round of the Invention This invention relates to a process for the manufacture of intermediates for ~-lactam antibiotics.
In particular, it relates to an improved process for the manufacture of 7-substituted amino-3-hydroxy-3-cephem-4-protected carboxy sulfoxide esters.
The preparation of 3-exomethylenecepham sulf-oxide esters is carried out by the known two-step process which comprises the conversion of a penicillin sulfoxide ester to a chlorosulfinylazetidinone followed by the cyclization of the latter to a 3-exomethylenecepham sulfoxide ester. The penicillin sulfoxide ester is converted to the intermediate chlorosulfinylazetidinone with an N-chloro halogenating agent as described by Kukol ja in U.S. Patent No.
4,165,315. The 4-chlorosulfinyl-azetidinone intermediates are described and claimed by Ku~olja in U.S. Patent No. 4,081,440. Chou, U.S. Patent No.
4,075,203, describes the preparation of 3-exomethylene-cepham sulfoxide ester via conversion of the penicillin sulfoxide ester in step 1 to the 4-chlorosulfinyl-azetidinone with an N-chloro halogenating agent in the presence of an alkylene oxide and calcium oxide. Later, Chou, U. S . Patent No. 4,289,695, describes an improved process for 3-exomethylenecepham sulfoxide esters by employing an acid scavenging cross-linked polyvinylpyridine polymer in step 1.

Kukolja, U.S. Patent No. 4,052,387, describes the cyclization of 4-chlorosulfinylazetidinones with a Lewis acid-type Friedel-Crafts catalyst, a sronsted proton acid-type Friedel-Crafts catalyst or with a metathetic cation-forming agent. Subsequently, Chou, U.S. Patent No. 4,190,724, describes and claims an improved process which comprises carrying out the Kukolja Friedel-Crafts catalyzed cyclization of a 4-chlorosulfinylazetidinone in the presence of oxo compounds such as ethers, ketones or phosphine oxides.
Copp et al., U.S. Patent No. 4,950,753, incorporated herein by reference, describe a further improvement of the Kukolja process which comprises carrying out the Friedel-Crafts cyclization in the presence of both an oxo compound of Chou and an unsaturated compound e.g., an alkene such as 1- or 2-hexene, a non-conjugated alkadiene such as 1,4-hexadiene, a cycloalkene such as cyclohexene, an allene, or a non-conjugated cycloalkadiene such as 1,4-cyclohexadiene.
As taught by Kukolja, U.S. Patent 4,052,387 and also by Chou, U.S. Patent 4,190,724, a tin-containing complex is formed when using a tin-containing catalyst such as stannic chloride. The following illustrates such, and also the further processing applied to form the 3-exomethylenecephemsulfoxide, as taught by Chou:

x-8728 ~3-Scheme I
o R2~S-CI

0 \C/~CH

¦ SnC4 ~¦, Inert organic solvent [Tin containing complex ] (b) ~N ~eCH2 ( c ) COOR~
¦ 1) Isolate ~ 2~03 OH (d) COOR~
(R~ is a protected amino and Rl is a carboxy-protecting group~.

X-87~S -4-In Scheme I, the 4-chlorosulfonylazetidinone (a) is combined with a tin-containing catalyst in an inert organic solvent to form a tin-containing complex intermediate. As noted in Chou 4,190, 724, the complex may be isolated by filtering the reaction mixture, cooled, and stored for further use. An alternative, as shown in Scheme I, includes adding methyl alcohol to the reaction mixture to decompose the complex to provide the corresponding exomethylene cepham-sulfoxide (c).
Thereafter, as has been taught in the prior art, the 3-exomethyienecepham sulfoxide ester (c) is first isolated and then subjected to ozone to form 3-hydroxy-3-cephem-sulfoxide ester (d). The sulfoxide ester (d) may be reduced by known techniques, such as with phosphorus trichloride or phosphorus tribromide in DMF, to provide the 3-hydroxy-3-cephem ester, a useful intermediate in the production of antibiotics, such as cefaclor.
Heretofore it has been taught that the tin-containing complex had to be decomposed so that isolation of the 3-exomethylene sulfoxide ester could occur before further processing steps, such as ozonolysis, could be taken. However, the present invention affords a novel process which avoids the requirement of isolating the 3-exomethylene cepham sulfoxide ester prior to further processing, thus allowing a more efficient and streamlined process.

X-8,~8 -5-Description of the Invention The process of this invention provides a 3-hydroxy-3-cephem sulfoxide ester represented by the formula 1:

HF~S~ ( 1 ) N ~OH

wherein A is an amino protecting group or a group of the formula 1l R-C-wherein R is the residue of a carboxylic acid RCOOH; and R1 is a carboxy-protecting group, by reacting an intermediate complex comprising a tin-containing Lewis acid-type Friedel-Crafts catalyst and a compound of the formula (2) O

H ~ S ~

(2) N ~ CH2 COOR~

with ozone, under substantially anhydrous conditions.
As is known in the art, the compound of formula 1 may also exist in the 3-keto tautomeric form, S and this tautomer is defined to be encompassed by the formula (1).
The term ~'residue of a carboxylic acid~
includes those 7-position side chains known in the cephalosporin and carbocephalosporin arts, and those 6-position side chains known in the penicillin art.Normally, these side chains are residues of C1-C20 carboxylic acids, and are exemplified when R is hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, Cl-C4 alkoxy, Cl-C4 alkylthio, trifluoromethyl, or trifluoro-methylthio; naphthyl, a phenyl or substituted phenyl group of the formula \~
a' ~ ~

wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, C1-C4 alkanoylamino, C1-C4 alkyl-sulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, carboxymethyl, C1-C4 haloalkyl or Cl-C4 perhalo-alkyl; a group of the formula \~
(Z)m~CH2~
a' ~
wherein a and a' have the same meanings as defined above, Z is O or S, and m is 0 or 1; an arylmethyl group of the formula wherein R is naphthyl, thienyl, furyl, benzothienyl, benzoaminothiazyl, benzofuryl, pyridyl, 4-pyridylthio, pyrimidyl, pyridazinyl, indolyl, pyrazoly~., imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such aryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl, or C1-C4 alkylsulfonylaminoi a sub-stituted methyl group of the formula I

Q
wherein R4 is cyclohex-1,4-dienyl, a phenyl or substituted phenyl of the formula \F\

a' ~ ~ ~

wherein a and a' are as defined above, or R4 is R3 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, amino, sulfoamino, or a substituted amino group of the formula o RX 11 -NH-C--N--C--RY

wherein Rx is hydrogen or C1-C3 alkyl, RY is Cl-C4 alkyl, furyl, thienyl, phenyl, halophenyl, nitrophenyl, styryl, halostyryl, nitrostyryl or a group of the formula RX
--N--RZ

wherein Rx has the same meanings as defined above and RZ
is hydrogen, C1-C3 alkylsulfonyl, C1-C3 alkyl, or C1-C4 alkanoyl; or Q is a substituted amino group of the formula O
o IL
-NH--C--N N-RZ

~ (CH2)q wherein RZ has the same meaning as defined above, and q is 2 or 3; or Q is a substituted amino group of the formula -NH(=O)--N~ ~N--C~ C4 alkyl or Q is a benzamido group of the formula --NH /=\~(OH)3 0~

wherein X is 1 to 3;
or Q is a pyridone or hydroxy-substituted pyridonyl-carbonylamino group of the formula H ~ - OH

wherein Rx is as defined above;
or Q is a pyridylcarbonylamino group of the formula o,9 ~

--NH l~N~J

such group optionally substituted by Cl-C4 alkyl, amino, carboxy, hydroxy or halogen; or Q is an imidazolyl or pyrazolyl group of the formula h i x-8728 -] O-o r ~I~N

H H

and such imidazolyl or pyrazolyl optionally substituted by C1-C4 alkyl, carboxy, amino, or halogen; or Q is a benzpyridazin-4-one group or tautomer thereof represented by the formula HO~ H

or HO ~ ~ ,H

O O

wherein Rx is as defined above, and t is 1 to 3; or Q is a benzpyranone group of the formula ~ t,' ~. , , , .:

H ~ OoH

O O

or R is a group of the formula R5-C- Rs-C- ' orR5- ICl-O N` C
OR6 R / \R

wherein Rs is R3 or R4 as defined above , R12 is hydrogen or halogen, and R6 is hydrogen, C1-C4 alkyl, C1-C4 alkyl substituted by halogen, a carboxy-substituted alkyl or cycloalkyl group represented by the formula b --C--(cH2)-ncoR7 wherein b and b~ independently are hydrogen or C1-C3 alkyl, n is 0, 1, 2, or 3; and b and b~ when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, and R7 is hydroxy, C1-C4 amino, C1-C4 alkylamino, or di(C1-C4 alkyl)amino;
or R6 is C1-C4 substituted by phenyl or phenyl substi-tuted by one or two of the same or different groupsselected from among C1-C4 alkyl, hydroxy, halogen, carboxy or protected carboxy; or R6 is C1-C4 alkyl substituted by amino or protected amino; or R6 is C1-C4 " ~ r~
X-872~ -12-alkenyl; or R6 is a cyclic lactam group of the formula (CH ~
~o wherein v is 2-4 and R8 is hydrogen or C1-C3 alkyl; or R6 is an aryl methyl group of the formula wherein R3 has the same meanings as defined herein above.
The term llcarboxy-protecting group" as used in the specification refers to one of the ester derivatives of a carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methylbenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethyl-benzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4l-dimethoxybenzhydryl, 2,2',4,4~-tetra-methoxybenzhydryl, t-butyl, t-a~yl, trityl, 4-methoxy-trityl, 4,4'-dimethoxytrityl, 4,4l,4ll-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, ~-(di(n-butyl)methyl-silyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-~ ., ~.- i ,: 5 x-87~8 -13-(trimethyisilylmethyl)prop-1-en-3-yl, and like moieties.
The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the ring system and can be removed at the appropriate point without disrupting the remainder of the molecule. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect carboxy group substituents of the azetidinone. Further examples of these groups are found in E. Haslam, ~Protective Groups in Organic Chemistry~, J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, ar,d T.W. Greene, ~Protective Groups in Organic Synthesis~, John Wiley and Sons, New York, N.Y., 1981, Chapter 5. The related term llprotected carboxy~ denotes that a carboxy group is substituted with one of the above carboxy-protecting groups. A preferred carboxy-protecting group is p-nitrophenyl.
The term "amino-protecting group~' refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the groups.
Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. W.
Barton, ~Protective Groups In Organic Chemistryl~, J. G.

x-8723 -14-W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7. The related term ~protected amino"
denotes that an amino is substituted with an amino-protecting group discussed above.
In the above definition of the compounds represented by the formula (1~, Cl-C6 alkyl refers to the straight and branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, and like alkyl groups;
Cl-C6 alhyl substituted by cyano refers to cyanomethyl, cyanoethyl, 4-cyanobutyl, and the like; Cl-C6 alkyl substituted by carboxy refers to such groups as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, and the like; Cl-C6 alkyl substituted by halogen refers to chloromethyl, bromomethyl, 2-chloroethyl, l-bromoethyl, 4-chlorobutyl, 4-bromopentyl, 6-chlorohexyl, 4-fluorobutyl, 3-fluoropropyl, fluoromethyl, and the like; Cl-C6 alkyl substituted by amino refers to such groups as 2-aminoethyl, aminomethyl, 3-aminopropyl and 4-aminobutyl;
Cl-C6 alkyl substituted by Cl-Cq alkoxy refers to methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, ethoxymethyl, 3-propoxypropyl, 3-ethoxybutyl, 4-t-butyloxybutyl, 3-methoxypentyl, 6-methoxyhexyl, and like group; Cl-C6 alkyl substituted by Cl-C4 alkylthio refers to such groups as for example methylthiomethyl, 2-methylthioethyl, 2-ethylthiopropyl, 4-methylthiobutyl, 5-ethylthiohexyl, 3-t-butylthiopropyl, and like groups;

X-8, 2~ -15-C1-C6 alkyl substituted by trifluoromethyl is exemplified by 2, 2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and the like; and C1-C6 alkyl substituted by trifluoromethylthio refers to, for example, trifluoromethylthiomethyl, 2-trifluoromethylthioethyl, 2-trifluoromethylthiopropyl, 4-trifluoromethylthiobutyl, 5-trifluoromethylthiohexyl, and like C1-C6 alkyl substituted groups.
When in the formula (1) A is a group of the formula o R-C-and R is a substituted phenyl group wherein the substi-tuent(s) are represented by a and a~, examples of such groups are halophenyl such as 4-chlorophenyl, 3-bromo-phenyl, 2-fluorophenyl, 2,4-dichlorophenyl, and 3,5-di-chlorophenyl; hydroxyphenyl such as 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, and 3,4-dihydroxyphenyl; alkoxyphenyl, such as 2,6-di-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butyloxyphenyl, 4-methoxy-3-ethoxy-phenyl, and 4-n-propoxyphenyl; alkanoyloxyphenyl such as 2-acetoxyphenyl, 4-propionoxyphenyl, 4-formyloxyphenyl, 4-acetoxyphenyl, 3-butyryloxyphenyl, and 3-acetoxyphenyl; alkylphenyl such as 4-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 3-t-butylphenyl, 4-ethylphenyl, 4-ethyl-3-methylphenyl, and 3,5-dimethylphenyl; alkylthiophenyl such as 4-methylthiophenyl, 3-n-butylthiophenyl, 2-ethyl-thiophenyl, 3,4-dimethylthiophenyl, and 3-n-propylthio-f . ~ b x-8728 -16-phenyl; aminophenyl such as 2-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl, and 3-aminophenyl;
alkanoylamino such as 2-acetylamino, 4-acetylamino, 3-propionylamino, and 4-butyrylamino; alkylsulfonylamino such a 3-methylsulfonylamino, 4-methylsulfonylamino, 3,5-(dimethylsulfonylamino)phenyl, 4-n-butylsulfonylaminophenyl, and 3-ethyl-sulfonylaminophenyl; carboxyphenyl such as 2-, 3-, or 4-, carboxyphenyl, 3,4-dicarboxyphenyl, and 2,4-dicarboxy-phenyl; carbamoylphenyl such as 2-carbamoylphenyl, 2,4-dicarbamoylphenyl, and 4-carbamoylphenyl; hydroxymethyl-phenyl such as 4-hydroxymethylphenyl and 2-hydroxymethylphenyl; aminomethylphenyl such as 2-aminomethylphenyl and 3-aminomethylphenyl; and carboxyphenyl such as 2-carboxymethylphenyl, 4-carboxymethylphenyl, and 3,4-dicarboxymethylphenyl; and the substituted phenyl groups bearing different substituents such as 4-chloro-3-methylphenyl, 4-fluoro-3-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 4-hydroxy-3-chlorophenyl, 4-hydroxy-3-methylphenyl, 4-ethyl-3-hydroxyphenyl, 4-methoxy-3-hydroxyphenyl, 4-t-butyloxy-2-hydroxyphenyl, 4-acetylamino-3-methoxyphenyl, 3-amino-4-ethylphenyl, 2-aminomethyl-4-chlorophenyl, 2-hydroxymethyl-3-methoxyphenyl, 2-hydroxymethyl-4-fluorophenyl, 2-acetoxy-4-aminophenyl, 4-acetoxy-3-methoxyphenyl, 3-isopropylthio-4-chlorophenyl, 2-methylthio-4-hydroxymethylphenyl, 4-carboxy-3-hydroxy-phenyl, 4-ethoxy-3-hydroxyphenyl, 4-methylsulfonylamino-2-carboxyphenyl, 4-amino-3-chlorophenyl, and 2-carboxy-methyl-4-hydroxyphenyl.

r~
X-872~3 -17 -When R iS a substituted phenyl group and a' or a is a Cl-C4 haloalkyl or Cl-C4 perhaloalkyl, examples of such substituents include chloromethyl, iodomethyl, trichloromethyl, trichloroethyl, 2-bromo-2-methylpropyl, chloropropyl, and fluoromethyl.
Examples wherein R is a group represented by the formula a\/=\
~ (Z)m~CH2~
a' with m = 0 are: phenylacetyl, 4-hydroxyphenylacetyl, 4-chlorophenylacetyl, 3,4-dichlorophenylacetyl, 4-methoxy-phenylacetyl, 3-ethoxyphenylacetyl, 2-aminomethylphenyl-acetyl, 3-carboxyphenylacetyl, 4-acetoxyphenylacetyl, 3-aminophenylacetyl, and 4-acetylaminophenylacetyl; and with m = 1 and Z = 0, phenoxyacetyl, 4-chlorophenoxyacetyl, 4-fluorophenoxyacetyl, 3-aminophenoxyacetyl, 3-hydroxyphenoxyacetyl, 2-. methoxyphenoxyacetyl, 2-methylthiophenoxyacetyl, 4-acetylaminophenoxyacetyl, 3,4-dimethylphenoxyacetyl, and 3-hyuroxymethylphenoxyacetyl; and with m = 1 and Z = S, phenylthioacetyl, 4-chlorophenyl-thioacetyl, 3,4-dichlorophenylthioacetyl, 2-fluorophenyl-thioacetyl, 3-hydroxyphenylthioacetyl, and 4-ethoxyphenyl-thioacetyl.
Examples when R is R3CH2- wherein R3 is an aryl group are: naphthyl, 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl, 2-benzothienylacetyl, 2-benzofurylacetyl, indol-2-ylacetyl, lH-tetrazol-l-~-3 8 -1~-ylacetyl, oxazol-2-ylacetyl, oxazol-4-ylacetyl, thiazol-4-ylacetyl, 2-amino-thiazol-4-ylacetyl, 1,3,4-oxadiazol-2-ylacetyl, 1,3,4-thiadiazol-2-ylacetyl, 5-ethyl-1,3,4-thiadiazol-2-ylacetyl and benzoaminothiazoyl, and like aryl groups optionally substituted by amino, Cl-C4 alkylsulfonylamino, hydroxy, halo, Cl-C4 alkyl or Cl-C4-alkoxy groups.
Examples wherein R is a substituted methyl group represented by the formula R-CH(Q)- and Q is amino, carboxy, hydroxy, or sulfo, are 2-carboxy-2-phenylacetyl, 2-carboxy-2-(4-hydroxyphenyl)acetyl, 2-amino-2-phenyl-acetyl, 2-amino-2-(4-hydroxyphenyl)acetyl, 2-amino-2-(3-chloro-4-hydroxyphenyl)acetyl, 2-amino-2-(cyclohex-1,4-dien-1-yl)acetyl, 2-hydroxy-2-phenylacetyl, 2-formyloxy-2-phenylacetyl, 2-sulfo-2-phenylacetyl, 2-sulfo-2-(4-methylphenyl)acetyl, and 2-acetoxy-2-(3-hydroxyphenyl)acetyl, 2-amino-2-(2-thienyl)acetyl, 2-amino-2-(3-benzothienyl)acetyl, 2-amino-2-(lH-tetrazol-l-yl)acetyl, 2-hydroxy-2-(1,3,4-thiadiazol-2-yl)acetyl, 2-amino-2-(2-aminothiazol-4-yl)acetyl, 2-carboxy-2-(2-thienyl)acetyl, 2-carboxy-2-(benzothien-2-yl)acetyl, and 2-hydroxy-2-(benzofur-2-yl)acetyl; and when Q is a sub-stituted amino group represented by the formula RX
-NH-c(o)-N-c(o)-R`r examples of such acyl groups are 2-(N-methyl-N-benzoyl-carbamoylamino)-2-phenylacetyl, 2-(N-methyl-N-cinnamoyl-carbamoylamino)-2-(2-furyl)acetyl, 2-(N,N-dimethyl-x-8728 -19-carbamoylureido)-2-(4-chlorophenyl)acetyl, 2-[N-methyl-N-(2-chlorocinnamoyl)carbamoylamino]-2-(2-thienyl)-acetyl, and 2-(N-ethyl-N-acetylcarbamoylamino)-2-(4-hydroxyphenyl)acetyl; and when Q is a substituted amino group represented by the formula o -NH--C--~ N~

(cH2)q examples are 2-[(3-methylimidazolidin-2-one-1-yl)car-10- bonylamino]-2-phenylacetyl, 2-[(3-acetylimidazolidin-2-one-l-yl)carbonylamino]-2-phenylacetyl, 2-[(3-methylsulfonyl-imidazolidin-2-one-1-yl)-2-(2-thienyl)acetyl, and 2-[(3-acetylhexahydropyrimidin-2-one-l-yl)carbonylamino]-2-phenylacetyl; and when Q is a hydroxy-substituted benzamido group represented by the formula --NH /=\/(OH)3 \ / \
0~

examples of such acyl groups are 2-(2,4-dihydroxy-benzamido)-2-phenylacetyl, 2-(4-hydroxybenzamido)-2-(4-hydroxyphenyl)acetyl, 2-(3,4-dihydroxybenzamido)-2-(2-aminothiazol-4-yl)acetyl, 2-(3,5-dihydroxybenzamido)-2-(3-thienyl)acetyl, and 2-(2-hydroxybenzamido)-2-(2-benzofuryl)acetyl.

~ ~y ~ ,i `3 x-8728 -'~

When Q is an hydroxy-substituted pyridinecarbonylamino group, examples include e.g., 2-hydroxypyridin-4-one-6-ylcarbonylamino and 3-hydroxypyridin-4-one-6-ylcarbonylamino. When Q is a pyridylcarbonylamino group examples are e.g., pyridin-3-ylcarbonylamino, 4-aminopyridin-3-ylcarbonylamino, 5-chloropyridin-2-ylcarbonylamino, 3-carboxypyridin-4-ylcarbonylamino, and 4-aminopyridino-2-ylcarbor.ylamino.
When Q is an imidazole or pyrazole group as defined above examples include e.g., 2-aminoimidazol-4-ylcarbonylamino, 5-carboxy-2-methylimidazol-4-ylcarbonylamino, 5-carboxypyrazol-3-ylcarbonylamino, 3-aminopyrazol-4-ylcarbonylamino and 4-hydroxypyrazol-5-ylcarbonylamino. When Q is a benzpyridazin-4-one-3-ylcarbonylamino group, examples of Q are represented bythe formulae HO ~--C-NH-and HO ~C-NH-OH

~ U ~

Examples when R is a keto group or an oximino-substituted group represented by the formulae 11 and 11 O N
~OR6 are the keto groups 2-oxo-2-phenylacetyl, 2-oxo-2-(2-thienyl)acetyl, 2-oxo-2-(2-aminothiazol-4-yl)acetyl; and oximino-substituted groups 2-phenyl-2-methoxyiminoacetyl, 2-(2-thienyl)-2-ethoxyiminoacetyl, 2-(2-furyl)-2-methoxyiminoacetyl, 2-(2-benzothienyl)-2-carboxymethoxyiminoacetyl, 2-(2-thienyl)-2-(2-carboxyethoxy)iminoacetyl, 2-(2-amino-1,2,4-thiadiazol-4-yl)-2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-methoxy-iminoacetyl, 2-~2-chlorothiazol-4-yl)-2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-yl)oxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-(2-carbamoyl-prop-2-yl)oxyimino-acetyl, 2-(5-amino-1,3,4-thiadiazol-2-yl)-2-methoxyiminoacetyl, 2-(2-. aminothiazol-4-yl)-2-(pyrrolidin-2-one-yl)-oxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-(1-methyl-pyrrolidin-2-one-3-yl)oxyiminoacetyl, 2-phenyl-2-(pyrro-lidin-2-one-3-yl)oxyiminoacetyl, 2-(2-aminooxazol-4-yl)-2-(1-ethylpyrrolidin-2-one-3-yl)oxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-(1-ethylpiperidin-2-one-3-yl)-2-oxyiminoacetyl, and 2-(2-furyl)-2-(pyrrolidin-2-one-3-yl)oxyiminoacetyl.

rJ
J
x-87~8 -22-Examples when R is a group of the formula R, / R~

may be found in Hamashima, U. S . Patent ~o. 4,634,617, incorporated herein by reference. Exemplary substituents are for R12, hydrogen, for Rs, phenyl, furyl, thienyl, oxazolyl, isoxazolyl, optionally protected aminoisoxazolyl, thiazolyl, optionally protected aminothiazolyl, thiadiazolyl, and aminothiazolyl, and for R6, C1-C3 alkenyl, especially methylene.
When R6 is C1-C4 alkyl substituted by phenyl or substituted phenyl, such groups are exemplified by benzyl, 4-hydrox~benzyl, 4-chlorobenzyl, 3-carboxybenzyl, 3-chloro-4-hydroxybenzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-hydroxy-2-phenylpropyl, 3-phenylbutyl and like phenylalkyl groups.
When R6 represents C1-C4 alkyl substituted by amino or protected amino, examples include 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-aminopropyl and such groups wherein the amino group is protected by an amino-protecting group.
When R6 is a C2-C4 alkenyl group, examples include allyl, butene-2, butene-3, butene-1, and like groups.

Preferred groups for A are those where A is R-C -and R is ~o--CH2 GrCH2 The tin-containing Lewis acid-type Friedel-Crafts catalysts are characterized by the presence of a vacant orbital which can accept an available electron pair, either unshared, e.g. on an oxygen, sulfur, or halide atom, or in a ~ orbital, of a Lewis base-type compound to form a covalent bond. Examples of suitable catal~sts are stannic chloride and stannous chloride.
Stannic chloride is preferred. The catalyst employed is preferably in an amount of between about 1.0 and 3 moles per mole of sulfinyl chloride (a).
4-Chlorosulfinylazetidinones of formula (a) used in the process are known compounds and, for example, are described by Kukol ja in U.S. Patent No.
4,081,440, incorporated herein by reference. Examples of the starting materials which are used in the process are t-butyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-r~

X-872~

phenylacetylamino-1-azetidinyl)-3-butenoate, t-butyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-phenoxyacetylamino-1-azetidinyl)-3-butenoate, diphenylmethyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-phenoxyacetylamino-1-azetidinyl)-3-butenoate, p-methoxybenzyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-phenylacetylamino-1-azetidinyl)-3-butenoate, p-nitrobenzyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-phenoxyacetylamino-1-azetidinyl)-3-butenoate, diphenylmethyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-benzoylamino-1-azetidinyl)-3-butenoate, p-nitrobenzyl 3-methyl-2-[4-chlorosulfinyl-2-oxo-3-(-t-butyloxycarbonylaminophenylacetylamino)-1-azetidinyl]-3-butenoate, benzyl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-phenoxyacetylamino-1-azetidinyl)-3-butenoate, and benzhydryl 3-methyl-2-(4-chlorosulfinyl-2-oxo-3-acetylamino-1-azetidinyl)-3-butenoate. Preferred azetidinones are represented by formula (a) where A iS a group of the formula o R-C-and R is benzyl, phenoxymethyl, phenylmethyl, or thienylmethyl. A preferred ester group R1 of formula (a) is benzyl or substituted benzyl, especially p-nitrobenzyl.
The cyclization process is carried out at atemperature between about -15C and about 60C and in an inert organic solvent. Solvents which may be used are described by Kukol ja in U.S. Patent No. 4,052,387, which is incorporated herein by reference and wherein the X-87~ -25-basic process is described. Solvents include ethyl acetate, the aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and the like, and the halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, and the like.
As noted above, the cyclization process is carried out under substantially anhydrous conditions.
Trace amounts of water are tolerable; however, it is desirable to maintain the reaction mixture in the cyclization process as dry as possible.
The cyclization process may take place in the presence of a nitro compound. The nitro compounds include Cl-C6 nitroalkanes and nitro substituted aryls, and are represented by nitromethane, nitroethane, 1-nitropropane, 2-nitropropane, p-nitrotoluene, alpha-nitrotoluene, and nitrobenzene. Nitromethane, 1-nitropropane, nitroethane, and nitrobenzene are preferred. Nitromethane is especially preferred. The nitro compound employed is preferably in the amount of between about 1 and about 4 moles per mole of the sulfinyl halide (a).
In another embodiment, an oxo compound is present during the cyclization. The oxo compounds used in the process are described by Chou, U.S. Patent No.
4,190,724, which is incorporated herein by reference, and are selected from among the group ~ O ~
R2O-R2,Z O,R2C-R2,z~ C=O a~ (R2)3P o, 'f I ~ J~ ~) X - 8 ~ 2 ~3 - 2 6 ~

wherein each R2 iS independently Cl-C4 alkyl; each R' 2 iS
independently Cl-C4 alkyl, C5-C6 cycloalkyl, phenyl or phenyl substituted by Cl-C4 alkyl, Cl-C4 alkoxy, or halogen; Z is tCH~m, -CH2-CH2-O-CH2-CH2-~ or -CH2-O-CH2CH2CH2-; m is 4 or 5; and Z' is ~ R

~ R2 / n wherein each of R2 is hydrogen or Cl-C4 alkyl, and n is 3 to 6. Preferred oxo compounds are diethyl ether, di-n-propyl ether, acetone and methylethyl ketone.
Especially preferred is diethylether. The oxo compound employed in the process is preferably in an amount corresponding to between about 0.75 and about 2 moles per mole of the sulfinyl chloride (a).
In another embodiment, an unsaturated compound is present during the cyclization. The unsaturated compound which can be used in the process may be selected from among C2-Clo olefins, Cs-Clo cycloolefins, non-conjugated Cs-Clo diolefins, C3-Clo allenes, and non-conjugated C6-Clo cyclodiolefins. Examples of such alkenes, alkadienes, cycloalke~es, allenes and cyclodienes include, for example, the alkenes ethylene, propylene, l-butene, 2-butene, l-pentene, 2-pentene, 1-hexene, 3-hexene, l-heptene, 3-heptene, l-octene, 2-nonene, 3-nonene, l-decene, 5-decene, and like terminal , ~ 3 ~ 4 ' ~ r~

X-S )S - 7-and non-terminal alkenes; non-conjugated alkadienes such as 1,4-pentadiene, l,4-hexadiene, 3-methyi-1,4-hexadiene, l,S- hexadiene, l,5-heptadiene, l,6-heptadiene, and like dienes; non-conjugated cyclodienes such as l,4-cyclohexadiene, l,4-cycloheptadiene, and the like; allenes such as allene, methylallene (1,2-butadiene), dimethylallene (2,3-pentadiene), and the like; cycloalkenes such as cyclopentene, l-methylcyclo-pent-2-ene, cyclohexene, cycloheptene, cyclooctene, and the like. The alkene, alkadiene or allene may be straight chained or branched and may be substituted with an inert group, preferably on a saturated carbon atom of the alkene. For example, the unsaturated compound may be substituted with alkyl such as methyl, ethyl or iso-propyl; halogen (preferably in a non-allylic position);
an esterified carboxy group; an aromatic group such as phenyl or tolyl; nitro; cyano; and alkoxy such as methoxy or ethoxy; and like aprotic substituents which are inert under the conditions of the process.
Non-terminal alkenes may be used in either the cis or trans forms. Preferred unsaturated compounds of the invention are the alkenes, e.g., l-pentene, 2-pentene, l-hexene, 2-hexene, l-heptene, l-octene and 1-decene; and the cycloalkenes, cyclopentene and cyclohexene. Especially preferred is l-hexene.
The unsaturated compound employed in the process is preferably present in an amount corresponding to between about one mole to about two moles per mole of sulfinyl chloride (a). An especially preferred amount is between about one mole and about 1.5 mole of x-8728 -28-unsaturated compound per mole of sulfinyl chloride (a).
Best results are achieved with 1 mole of unsaturated compound, expecially 1-hexene, per mole of the compound of formula (aj.
In an other embodiment of the cyclization, a 4-chlorosulfinylazetidin-2-one of formula (a~ is reacted with between about 1.5 and about 3 moles of stannic chloride per mole of the azetidinone, between about 0.75 and about 2 moles of ethyl ether per mole of the azetidinone, between about 1 and 2 moles of 1-hexene per mole of the azetidinone, and about 1 to 4 moles of nitromethane per mole of the azetidinone, in an inert - solvent under substantially anhydrous conditions at a temperature between about -10C and about 0C.
The formation of the complex is carried out generally as follows. The 4-chlorosulfinylazetidinone (a) is dissolved in an anhydrous inert organic solvent.
The solution is cooled preferably to a temperature of about 0C to about 15C. The above mentioned compounds may be added to the solution, cooled to about -10C, and stirred. The catalyst is cooled to about -10C and added to the mixture. The solution is stirred under nitrogen and allowed to reach about room temperature (18-24C).
While the complex may be filtered, no further isolation or decomposition of the tin-complex(tin-containing catalyst/3-exo-methylene cepham) need be carried out. The complex formed is then subjected to ozone, in situ. A distinguishing feature of the invention is the obviation of the decompostion or rl ~~
~-8728 ~~9 -further isolation of the 3-exomethylene cepham from the tin-complex prior to ozonolysis. Therefore, the amount of catalyst is present in a generally stoichiometric amount, or more than just trivial or minute amounts as might be expected after isolation procedures are carried out according to the previously cited references.
Another feature of the invention is the temperature to be used in an ozonolysis, which should be as cold as possible. For current practical production, the temperature range should be about -70 to -5C, with a temperature range of -70 to -30C being preferred. A
more preferred temperature range for the ozonlysis is between about -50 to about -35C. In particular, the temperature used in the in situ ozonolysis is based on the freezing point of the tin-complex/solvent mixture, and the cost related to cooling versus the increase in yield at the lower temperature. As the temperature was lowered for the ozonolysis, surprisingly high yields were obtained. Preferred solvents for the ozonolysis include ethyl acetate and methylene chloride, with ethyl actate being more preferred.
The tin-complex, or tin-containing intermediate, is formed from the addition of a tin-containing catalyst and 4-chlorosulfinylazetidine. The ring-closure or cyclization step has been studied to determine the nature of the tin complex. From the studies thus far indications are that initially a 4-chlorosulfinylazetidine/tin catalyst solid intermediate is formed, and, thereafter, under solid state conditions, the 3-exomethylene cepham sulfoxide/tin catalyst complex is formed. This latter intermediate is, under in-situ ozonolysis, transformed to the 3-hydroxy-3-cephem sulfoxide ester/tin complex.
As described herein above anQ in the Examples, the process affords an effective method for producing 3-hydroxy-3-cephem sulfoxide ester (d) without the need to separate or decompose the complex formed prior to the compound~s (d) formation. The 3-hydroxy-3-cephem sulfoxide ester (d) may then be further processed to provide cephalosporin antibiotics. For example, the compound (d) may be reduced to the sulfide, c'nlorinated at the 3-position, and deesterified all by means known in the art, to produce, for instance, cefaclor.
The following Experimental Section provides further description of the invention but is not to be construed as limitations thereof.
Pre~aration 1 Methvl 3-Methvl-2-(2-chlorosulfinvl-4-oxo-3-imido-1-azetidinvl)-3-butenoate (refered to herein as sulfinyl chloride).

HN~ _____"S-CI

' I\~C-CH3 X-8,~8 -31-For preparation of the ti~led product, the process as disclosed in Chou, U. S . Patent No. 4,190,724 is employed.
5 The product has the following physical data.
H NMR: (CDCl3, 300 MHz, ppm) 1.92 (s, 3H, CH3), 4.50:4.56 (AB, 2H, J=15.1 Hz, side chain CH2), 4.99 (s, lH, olefinic CH2), 5.06 (s, lH, CHCOOpNB), 5.22 (d, lH, J=1.6 Hz, olefinic CH2), 5.25:5.33 (AB, 2H, J=12.9 Hz, pNB CH2), 5.53 (d, lH, J=4.6 Hz, azetidinone H), 6.27 (dd, lH, J=4.6 Hz and 10.8 Hz, azetidinone H), 6.90 (dd, 2H, J=7.4 Hz and 8.5 Hz, side chain ArH), 7.01 (t, lH, J=7.4, side chain ArH), 7.30 (dd, 2H, J=7.4 Hz and 8.5 Hz, side chain ArH), 7.50 (AA'BB', 2H, J=8.9 Hz, pNB ArH), 7.98 (d, lH, J=10.8 Hz, N-H), 8.23 (AA'BB', 2H, J=8.9 Hz, pNB ArH).
In the following preparations, the 20 intermediate tin complex is formed.

Pre~aration 2 A 500 ml three-necked round bottomed flask is equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer. The reaction flask is charged with 220 ml of a toluene solution of sulfinyl chloride (25.5 mmoles based on (lB)-6-[(phenoxyacetyl)amino]penicillanic acid, (4-nitrophenyl)methyl ester-1-oxide. In a separate 50 ml flask is added 10 ml of toluene and diethyl ether x-8728 -32-[2.5 ml (1.76 g) 23.9 mmoles~, and the solution is cooled to 0 to -5C. Tin (IV) chloride [5.1 ml (11.36 g) 43.6 mmoles] is added to the toluene/diethyl ether solution and the resultant slurry is immediately cooled to 0C with an acetone/dry ice bath. The toluene solution of sulfinyl chloride is cooled to 15C and the tin (IV) chloride/diethyl ether/toluene slurry is added to the sulfinyl chloride in 5 to 10 seconds using 5 ml of toluene rinse. The resultant slurry is allowed to exotherm to 21 to 23C and stir for 18 hours under nitrogen.

Pre~aration 3 Preparation 2 (above) is repeated except: the toluene solution of sulfinyl chloride is cooled to -50C
before the 0C tin (IV) chloride/diethyl ether/toluene slurry is added.

Pre~aration 4 Preparation 2 (above) is repeated except: the toluene solution of sulfinyl chloride is cooled to -10C
before the 0C tin (IV) chloride/diethyl ether/toluene slurry was added.
Pre~aration 5 Preparation 2 (above) is repeated except: no diethyl ether is utilized in the reaction.

? ~ r'~
x-872~ -33-Pre~aration 6 A 500 ml three-necked round bottomed flask is equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer. The reaction flask is charged with S 192 ml of a toluene solution of sulfinyl chloride (25.5 mmoles based on (lB)-6-[(phenoxyacetyl)amino]peni-cillanic acid, (4-nitrophenyl)methyl ester-1-oxide. In a separate 50 ml flask is added 10 ml of toluene. This toluene is cooled to 0 to -5C before tin ( IV) chloride [5.1 ml (11.36 g) 43.6 mmoles] is added. The resultant solution is immediately cooled to -10C with an acetone/dry ice bath. Nitromethane [3.5 ml (3.94 g) 64.6 mmoles] is added to the sulfinyl chloride solution and the resultant solution is cooled to -10C with an acetone~dry ice bath. The tin (IV) chloride/toluene solution is added to the -10C sulfinyl chloride solution in 5 to 10 seconds using 5 ml of toluene rinse.
The resultant slurry was allowed to exotherm to 21 to 23C and stir for four hours under nitrogen.
Preparation 7 Preparation 6 (above) is repeated except:
1-hexene [3.2 ml (2.17 g) 25.8 mmoles] is also added to the toluene solution of sulfinyl chloride prior to the tin (IV) chloride/toluene addition.

Preparation 8 A 500 ml three-necked round bottomed flask is equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer. The reaction flask is charged with x~ g-179 ml of a toluelle solutioll of sulfinyl chloride (2g.7 mmoles based on (lB)-6-~(phenoxyacetyl)amino]penicillanic acid, (4-nitrophenyl) methyl ester-1-oxide). In a separate 50 ml flask is added 10 ml of toluene and diethyl ether [2.4 ml (1.70 g) 22.9 mmoles], and the solution is cooled to 0 to -5C. Tin (IV) chloride [4.9 ml (10.91 g) 41.9 mmoles] is added to the toluene/diethyl ether solution and the resultant slurry is immediately cooled 10 to and held at 0C with an acetone/dry ice bath.
1-Hexene [3.1 ml (2.10 g) 25.0 mmoles] is added to the sulfinyl chloride solution and the resultant solution is cooled to 10C. The 0C tin (IV) chloride/diethyl ether/toluene slurry is added to the sulfinyl chloride 15 in 5 to 10 seconds using 5 ml of toluene rinse. The resultant slurry is allowed to exotherm to 21 to 23C
and stir for four hours under nitrogen.

Pre~aration 9 Preparation 6 (above) is repeated except:
diethyl ether [2.5 ml (1.76 g) 23.9 mmoles] is utili~ed as described in Preparation 2.

Pre~aration 10 A 500 ml three-necked round bottomed flask is equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer. The reaction flask is charged with 179 ml of a toluene solution of sulfinyl chloride (24.7 mmoles based on (lB)-6-30 [(phenoxyacetyl)amino]penicillanic acid, (4-nitrophenyl) r ~-87 '8 -35-methyl ester-1-oxide. In a separate 50 ml flask is added 10 ml of toluene and diethyl ether [2.4 ml (1.70 g) 22.9 mmoles], and the solution is cooled to 0 to -5C. Tin (IV) chloride [4.9 ml (10.91 g) 41.9 mmoles] was added to the toluene/diethyl ether solution and the resultant slurry is immediately cooled to and held at 0C with an acetone~dry ice bath. 1-Hexene [3.1 ml (2.10 g) 25.0 mmoles] and nitromethane [3.3 ml (3.72 g) 60.9 mmoles] are added to the sulfinyl chloride solution and the resultant solution was cooled to 0C with an acetone/dry ice bath. The 0C tin (IV) chloride/diethyl ether/toluene slurry is added to the 0C sulfinyl chloride in 5 to 10 seconds using 5 ml of toluene rinse. The resultant slurry is allowed to exotherm to 21 to 23C and stir for four hours under nitrogen.

Pre~aration 11 Preparation 6 (above) is repeated except:
diethyl ether [2.5 ml (1.76 g) 23.9 mmoles] is utilized as described in Preparation 1, and nitrobenzene [6.6 ml (8.21 g) 64.1 mmoles] is used in place of nitromethane.
The sulfinyl chloride/tin (IV) chloride/diethyl ether/toluene/ nitrobenzene slurry is also only allowed to stir for 90 minutes at 21 to 23C rather than four hours.

Pre~aration 12 Preparation 5 (above) is repeated except:
diethyl ether [2.5 ml (1.76 g) 23.9 mmoles] is utilized as described in Preparation 2, and 1-nitropropane [5.7 ml (5.68 g) 63.8 mmoles] is used in place of nitromethane. The sulfinyl chloride~tin (IV) chloride/diethyl ether/toluene/ 1-nitropropane slurry is also only allowed to stir for 90 minutes at 21 to 23C
rather than four hours.

Pre~aration 13 Preparation 6 (above) is repeated except:
diethyl ether [2.5 ml (1.76 g) 23.9 mmoles] is utilized as described in Preparation 2, and nitroethane [4.6 ml (4.80 g) 64.0 mmoles] is used in place of nitromethane.
The sulfinyl chloride/tin ~IV) chloride/diethyl ether/toluene/ nitroethane slurry is also only allowed to stir for 90 minutes at 21 to 23C rather than four hours.

,Exam~le 1 7-~(~henoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitro~henvl)methvlester, 1-oxide/tin com~lex To 30 g of 3-exomethvlenesulfoxide ester/tin complex is added 250 ml of ethyl acetate. The solution is added into an ozonolysis vessel along with a rinse (using around 50 ml of cold ethyl acetate). The solution is ozonized for 45 minutes after being cooled x-8728 ~37- ~ 7 to -5C. The resulting mixture (which is a slurry as the product formed is insoluble in ethyl acetate) is analyzed by HPLC. Ozonolysis is continued for another 30 minutes. The resulting mixture is purged with air until it is free from ozone and then 12.5 ml of cold triphenylphosphite (TPP~ is added dropwise while maintaining a temperature between 0 and -5C. The TPP
is added over a 38 minute period and then the resulting slurry is stirred for 10 minutes, vacuum filtered, and the filter cake washed with cold ethyl acetate. The cake is dried under vacuum, resulting in 20.96 g of the titled complex.

Exam~le 2 7~ henoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitro~henvl)methvlester, l-oxide The tin/complex, as prepared by any of preparations 2 through 13, is transferred to an ozonolysis vessel using ethyl acetate at -20C. While maintaining the temperature between -3C and -5C, the mixture is ozonized for 45 minutes after which it is analyzed for the progress of the reaction by HPLC, then ozonized for an additional 45 minutes. The reaction mixture is analyzed once more by HPLC . The final mixture is then transferred to a separate flask and, after reduction with 25 ml of TPP added over a period of 40 minutes, it is held at 0C. ~ethyl alcohol is added and the resulting mixture is stirred for 1 hour at which time 30 ml of deionized water is added and the mixture is stirred for another 15 minutes. An observation is that the 3-exomethylenesulfoxide ester/tin complex is soluble in ethyl acetate which results in a dark brown solution. Upon ozonolysis, the color of the solution changes to a straw yellow color. There was no precipitation observed during ozonolysis or methanolysis.

Exam~le 3 7~ henoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxYlic acid. (4-nitro~henvl)methvlester/tin com~lex 3-exomethylenesulfoxide ester/tin complex, as prepared in any of Preparations 2-13, in toluene is stirred for 21 hours and is then cooled to 15C and the mother liquor decanted with a gas dispersion tube/vacuum flask apparatus. The wet cake is dissolved in cold ethyl acetate (327 ml) and is transferred to the ozonolysis vessel along with the rinse. Upon cooling the solution to -3C, the solution is ozonized for 60 minutes. After purging for 10 minutes with air, 16.7 ml of TPP is added dropwise from a dripping funnel over a 35 minute period to result in a homogeneous mixture containing the title compound.

Exam~le 4 7-~(~henoxYacetvl)-aminol-3-hvdroxY-3-ce~h-4-carboxvlic acid (4-nitro~henvl)methvl ester l-oxide/tin com~lex Following a 16 hour stir at approximately 23C, the tin complex slurry in toluene is cooled to 15C, and the mother liquor is decanted from the tin slurly using a gas dispersion tube/vacuum flask X-S72S -39- ~ ~ c;~

apparatus. The wet solid is dissolved in 200 ml of ethyl acetate. The solution is then transferred to an ozonolysis vessel equipped with a thermometer and an overhead stirrer while air is passed into the vessel through a bottom valve. The flask is rinsed with 127 ml of ethyl acetate which is added to the ozonolysis vessel resulting in a 12.4% wtv solution. Deionized water (0.5 ml; 0.028 moles with respect to the Pen-V sulfoxide PNB
ester) was added to the resultant solution which is stirred while being cooled to -5C.
With continued stirring, the cold solution is ozonized using a laboratory ozone generator (6 SCFH air and 8 psi) for 45 minutes while the temperature is maintained between -5 and -3C. The reaction is checked for completeness by HPLC. If the reaction is not essentially complete, ozonolysis is continued. Triphenyl phosphite (16.67 ml) is added dropwise to the reaction mixture over 40 minutes while the temperature was maintained between 0 and 5C. The reaction mixture is then purged for 10 minutes befGre it is transferred to a 500 ml Erlenmeyer flask. Dimethylsulfoxide (DMSO) (19.8 ml; 2 molar equivalents with respect to stannic chloride used in the preparation of the tin complex) is added slowly with stirring to the ethyl acetate solution, then the resultant slurry is stirred for an additional 30 minutes. The white solid formed(SnCl4.2DMSO) is filtered, then washed with 50 ml of ethyl acetate prior to drying in vacuo at 50 degrees C. The filtrate is assayed for 3-hydroxycephem sulfoxide ester content by HPLC and a yield of 23-29~6 was obtained.

X-8~8 -40 Exam~le 5 7-~(~henoxvacetvl)-aminol-3-hvdroxv-3-ce~h-4-carboxvlic acid, (4-nitro~henvl)methvl ester, 1-oxide/tin com~lex Two separate batches of 3-exomethylene-3-cephem sulfoxide/tin complex are used. Both batches are stirred for more than 16 hrs, after which they are cooled to 15C and the mother liquor is decanted using a vacuum distillation/gas dispersion tube aparatus. The resulting wet cakes are dissolved in 200 ml of ethyl acetate each.
The first solution is placed in the ozonolysis vessel followed by 0.5 ml deionized water and the mixture is ozonized (6 SCFH and 8 psi) for 45 minutes.
The reaction is checked for completeness by HPLC. After cooling the solution to -3C, the resultant reaction mixture is quenched with 16.67 ml of TPP which is added dropwise over 40 minutes keeping the temperature between 0 and 5C. The mixture is then purged for 10 minutes, then transferred to a 500 ml Erlenmeyer flask. The mixture is left to stand at 0C overnight.
The first solution is transferred to an Erlenmeyer flask and 19.8 ml of DMSO is added slowly while stirring. The resulting slurry is stirred for 1/2 hour after which the reaction mixture is filtered. The filter cake is washed with 100 ml of fresh ethyl acetate. The beige solid obtained is dried in vacuo at 50C. The filtrate is concentrated and held at 0C.
The second solution is transferred to the ozonolysis vessel using 127 ml of ethyl acetate as wash X-8728 -41- ~ ~ c)~ `J 7 (12.4~6 wiv). Deionized water (0.5 ml) is added to the solution in the ozonolysis vessel. The resulting mixture is cooled to -3C and ozonized (6 SCHF, 8 psi).
The reaction mixture is quenched by dropwise addition of 16.67 ml of TPP over a 40 minute period.
The second resultant mixture is washed with three 100 ml aliquots of deionized water. The combined aqueous layers are then back extracted twice with 100 ml of ethyl acetate, then once with 50 ml of ethyl acetate.
The organic layers are combined. The resultant solution is divided into 2 portions. Each portion is further washed with 200 ml water. The aqueous layers are back extracted twice with S0 ml of ethyl acetate and combined with the organic layers. Each portion is again washed with 100 ml of water and both organic portions are then combined, stripped of solvent (concentrated) then held at 0C

Exam~le 6 7- r (~henoxvacetvl)-aminol-3-methvleneçe~hem-4-carboxvlic acid (4-nitro~henvl)methvl ester. 1-oxide/tin com~lex In a 3-necked, 1-liter round bottomed flask equipped with a mechanical stirrer, thermometer and a nitrogen purge, was added 20.7 g (40 mmoles) of 3-methylene-7-[(phenoxyacetyl)amino]cepham-4-carboxylic acid, (4-nitrophenyl)methyl est~r, 1-oxide (I) and 300 ml of methylene chloride. The resultant solution was cooled to 15C.
To a separate 100 ml round bottomed flask 20 ml of methylene chloride and 4.2 ml of diethyl ether was ~; ~ S ~ . r-adAed and the mi~ture cooled to 5C. Tin (IV) chloride (7.96 ml, 68 n~oies) was added to the 5C ether solution whereupon a slurry formed on cooling to 0C. This slurry was added to the rapidly stirring methylene chloride (I) solution and stirring was continued for 30 minutes at 23C. The solvent was decanted using a gas dispersion tube/vacuum flask apparatus. Hexane (250 ml) was added to the remaining wet cake and the resultant slurry stirred for 90 minutes at room temperature. The slurry was filtered. The filter cake (a white solid~
was washed with hexane and dried under vacuum at 23C
for approximately 16 hours. The yield was 22.97 g. The product melted with decomposition at approximately 139C
to 161.5C.
1H NMR: 2.5 ppm (s, DMSO), 3.33 (s, ?H), 3.86 (q, 2H), 4.65 (s, 2H, V (CH2)), 5.11 (d, lH), 5.35 (s, 2H), 5.42:5.77 (s:s, lH), 5.54 (s, lH), 5.85 (dd, lH), 6.99 (q, 3H), 7.33 (t, 2H), 7.68 (d, 2H), 8.27 (d, 2H), 8.29 (s, lH). MS: m/z (relative intensity) 500 (19), 475 (4), 365 (4), 333 (14), 309 (12), 192 (16), 155 (72), 151 (43), 135 (43), 119 (103), (60). IR: 3355.60 (NH
stretch), 2800 - 3200 (CH stretch), 1788.24, 1733 and 1680 (C=O stretch). Anal. Calcld for C23H21N3OgSSnCl4:
C, 36.35; H, 2.79; N, 5.53; O, 16.84; S, 4.22; Sn, 15.6;
Cl, 18.66. Found: C, 33.74; H, 3.19; N, 4.83; O, 21.73; S, 3.78; Sn, 15.4; C1, 17.77.

Exam~le 7 ~7-(~henoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitro~henvl)methvl ester (II) The tin/complex (20 g, 26.3 mmoles~ prepared in Example 6 was transferred to a 2 liter ozonolysis vessel using 161 ml of ethyl acetate (12.4% w/v solution). While maintaining the temperature between -5C and -3C, the resultant solution was ozonized for 45 minutes and the resultant slurry analyzed by HPLC.
The analysis indicated that 10% of (I) was still present. The reaction mixture was ozonized for an additional 30 minutes and analyzed again by HPLC. The analysis indicated that 2% of (I) was present. The slurry was then quenched by the dropwise addition of 25 ml of triphenyl phosphite (TPP) over 40 minutes while maintaining the temperature between 0C and 5C. The reaction was filtered and the wet cake washed with ethyl acetate. The filter cake was dried ln vacuo at 50C. A
total of 9.37 g (73.6% purity by HPLC analysis; 52%
corrected yield) was obtained. The product melted with decomposition at approximately 148C to 155C.
lH NMR: 2.50 ppm (s, DMSO), 4.03 (s, 2H), 4.70 (s, 2H, V(CH2)), 5.03 (d, lH), 5.50 (dd, 2H, PNB(CH2)), 5.93 (q, lH), 7.0 (q, 3H), 7.34 (t, 2H), 7.77 (d, 2H), 8.13 (d, lH), 8.27 (d, 2H), 11.18 (s, lHj; MS: m/e (relatively intensity) 502 (1), 4.75 (3), 351 (4), 333 (7), 309 (29), 307 (8), 157 (8), 155 (89), 135 (38), 119 (100) 103 (46); IR: 3307.38 (NH stretch), 2940.85 (CH
stretches), 1777.63, 1724.58 and 1679.25 (C=O

x-872~ -~4-stretches).
Anal.: C22H1gN3OgS
Calc~d : C, S2.69; H, 3.82; N, 8.38; O, 28.71i S, 6.93.
Found: C, 49.01; H, 3.88; N, 7.67; o, 28.07; S, 5.76.

Exam~le 8 ~ 7-(~henoxYacetYl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitro~henvl) meth~l ester (II) A tin complex was prepared on a 81.7 mmole scale as developed by Chou in U.S. 4,190,724. Following a 19.5 hour stir, the toluene slurry was cooled to 15C
followed by filtration. The wet cake was dissolved in 200 ml of ethyl acetate and transferred to the ozonolysis vessel using 127 ml of ethyl acetate to rinse (A 12.4% w/v solution with respect to the 1 resulted).
The brown solution was cooled to -3C and 0.5 ml (27.8 mmoles) of deionized water was added, then the solution was ozonized for 45 minutes. The reaction mixture was analyzed by HPLC after 30 and 45 minutes to determine the extent of the reaction (approximately 45% yield of (II) was formed after 45 minutes). While maintaining the temperature between 0C and 5C, TPP (16.7 ml, 19.7 g; 63.6 mmoles) was added dropwise to the resultant yellow solution over a 40 minute period then the mixture was purged with air for 10 minutes. The white precipitate was filtered. The ethyl acetate solution was analyzed for content of (II). The yield (15.8 g) and percent yield (38.7%) at this point was calculated against a standard using HPLC.

X-87~8 -45-The solution was transferred to an Erlenmeyer flask and 19.8 ml (17.9 g); 279 mmoles) of DMSO was added while stirring. The resultant slurry was stirred for 30 minutes then cooled to 0C. The slurry was filtered, washed with 60 ml of ethyl acetate. The ethyl acetate filtrate was determined by HPLC analysis to contain 14.0 g (34.2% yield) of (II). The white solid was dried in vacuo overnight at 50C yielding 56.7 g (97.7% yield) of solid, melting range of 237-239.5C.
Exam~le 9 ~7-(~henoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitro~henvl) methvl ester A tin complex was prepared on a 81.7 mmole scale as developed by Chou in U.S. 4,190,724. After an 18 hour stir, the tin slurry was cooled to 15C before transferring the toluene slurry to the ozonolysis vessel using 100 ml of toluene to rinse. Deionized water (0.50 ml, 28 mmoles) was added to the vessel after which the mixture was cooled to -5C, then ozonized for 60 minutes. The reaction mixture was analyzed by HPLC
after 30 and again af~er 60 minutes. Analysis of the reaction mixture by HPLC indicated that less than 1% of (II) had formed. Ethyl acetate (67 ml) was then added to the reaction mixture and ozonolysis continued for another 2 hours. The progress of the reaction was followed by HPLC - 100, 125, 150 and 180 minutes.
Another 100 ml of ethyl acetate was added to the reaction mixture and ozonolysis continued for another hour. The composition of the reaction mixture was x-8728 -46-determined by HPLC to be 21% (I) and 26.4% (II).

Exam~le 10 ~7-(Dhenoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitroDhenvl) methvl ester The experiment under Example 8 was repeated, except the mixture was ozonized for 35 minutes. The yield was 48.9~.

Exam~les 11 ~(Phenoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-ca~boxvlic acid, (4-nitro~henvl) methvl ester A tin complex was prepared on a 79.9 mmole scale as developed by Chou in US 4,190,724. Following a 17.25 hour stir, the toluene slurry was cooled to 15C
followed by filtration. The wet cake was dissolved in 200 ml of ethyl acetate and transferred to the ozonolysis vessel using 127 ml of ethyl acetate to rinse. The brown solution was cooled to -15C then the solution was ozonized for 30 minutes. The reaction mixture was analyzed by HPLC after 30 minutes to determine the extent of the reaction (approximately 62%
yield of titled product was formed after 30 mintues.) While maintaining the temperature between -5C and 0C, TPP (16.7 mL, 19.7 g; 63.6 mmoles) was added dropwise to the resultant yellow solution over a 40 minute period.
The yield (18.9g) and percent yield (47.1%) at this point was calculated against a standard using HPLC.
The solution was transferred to an Erlenmeyer flask and 19.8 ml ~17.9g); 279 mmoles of DMSO was added while stirring. The resultant slurry was stirred for 30 minutes then cooled to UC. The slurry was filtered, washed with lUU ml of ethyl acetate. The ethyl acetate filtrate was determined by HPLC analysis to contain 21.7g (54.2% yield) of the titled product. The white solid was dried in vacuo overnight at 5UC yielding 51.2g (88.2% yield) of solid (SnCl4.2(DMSO)), melting range of 274 - 275C.

1U Fxam~le 12 ~(Phenoxvacetvl)-aminol-3-hvdroxv-3-ce~hem-4-carboxvlic acid, (4-nitro~henvl) methvl ester (2) A tin complex was prepared on a 79.9 mmole scale as developed by Chou in US 4,19U,724. Following a 19.25 hour stir, the toluene slurry was cooled to 15C
followed by filtration. The wet cake was dissolved in 2U0 ml of ethyl acetate and transferred to the ozonlysis vessel using 127 ml of ethyl acetate to rinse. The brown solution was cooled to -40C then the solution was ozonized for 3U minutes while maintaining the temperature between -40C and -36C. The reaction mixture was analyzed by HPLC after 30 minutes to determine the extent of the reaction (approximately 71%
yield of titled product was formed after 30 minutes.) While maintaining the temperature below 0C, TPP 16.7mL, (19.7 g; 63.6 mmoles) was added dropwise to the resultant yellow solution over a 40 minute period. The ethyl acetate solution was analyzed for content of titled product. The yield (27.3g) and percent yield (68.1%) at this point was calculated against a standard X-~7~S -~8-usiny HPLC.
The solution was transferred to an Erlenmeyer flask and 19.8 ml (17.9g); 279 mmoles) of DMSO was added while stirring. The resultant slurry was stirred for 30 minutes then cooled to 0C. The slurry was filtered, washed with 100 ml of ethyl acetate. The ethyl acetate filtrate was determined by HPLC analysis to contain 29.lg (72.7% yield) of titled product. The white solid was dried in vacuo overnight at 50C yielding 49.3g (84.9%) of solid (SnCl4.2(DMSO)), melting range of 257.5

Claims (10)

1. A process for the preparation of a compound of the formula (1) wherein A is an amino protecting group or a group of the formula wherein R is the residue of a carboxylic acid RCOOH; and R1 is a carboxy-protecting group, comprising the step of reacting an intermediate complex comprising a tin-containing Lewis acid-type Friedel-Crafts catalyst and a compound of the formula (2) (2) with ozone, under substantially anhydrous conditions.

X-8728(EPO) -50-

2. The process as recited in Claim 1 wherein the catalyst is stannic chloride;
A is of the formula and R is or ; and R1 is p-nitrophenyl.

3. The process as recited in Claim 2 wherein the ozonolysis takes place in the presence of ethyl acetate or methylene chloride.

4. The process as recited in Claim 3 wherein the ozonolysis takes place at a temperature of between about -70 to about -5°C.

5. The process as recited in Claim 4 further comprising reducing the compound of formula (1) to result in a compound of the formula (3).

(3) ;
X-8728(EPO) -51-chlorinating the compound of formula (3) to give a compound of the formula (4) (4);
and deesterifying the compound of formula (4) to obtain a compound of formula (5) (5)

6. The process as recited in Claim 5 where A
is of the formula

7. In a process for preparing a compound the formula (1) X-8728(EPO) - 52 - wherein A is an amino protecting group or a group of the formula wherein R is the residue of a carboxylic acid RCOOH and R1 is a carboxy protecting group, by reacting a compound of the formula wherein R5 is A-?- or imido, with a tin-containing Lewis acid-type Friedel-Crafts catalyst, said reacting forming an intermediate complex comprising the catalyst and a compound of the formula (2) X-8728(EPO) -53- (2) the improvement characterized in ozonizing the intermediate complex without any substantial prior isolation of the compound of formula (2).

8. The process as recited in claim 7 wherein A is or or R1 is p-nitrophenyl; and the catalyst is stannic chloride

9. The process as recited in claim 8 further comprising reducing the compound of formula (1) to result in a compound of formula (3) X-8728 (EPO) -54-(3) ;
and desterifying the resultant compound to obtain a compound of formula (5) (5);

10. The process as recited in claim 9 wherein said ozonolysis takes place in the presence of ethyl acetate, and at a temperature of -50 to -35°C.